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WO2000066103A2 - Schemas posologiques cycliques comprenant de l'uree cyclique et des derives cycliques d'amide - Google Patents

Schemas posologiques cycliques comprenant de l'uree cyclique et des derives cycliques d'amide Download PDF

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Publication number
WO2000066103A2
WO2000066103A2 PCT/US2000/011449 US0011449W WO0066103A2 WO 2000066103 A2 WO2000066103 A2 WO 2000066103A2 US 0011449 W US0011449 W US 0011449W WO 0066103 A2 WO0066103 A2 WO 0066103A2
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Prior art keywords
alkyl
substituted
phase
daily dosage
alkoxy
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PCT/US2000/011449
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English (en)
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WO2000066103A3 (fr
Inventor
Gary S. Grubb
Lin Zhi
Todd K. Jones
Christopher M. Tegley
Zhang Puwen
Andrew Fensome
Andrew Q. Viet
Arthur A. Santilli
Eugene A. Terefenko
Jay E. Wrobel
James P. Edwards
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American Home Products Corporation
Ligand Pharmaceuticals, Inc.
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Application filed by American Home Products Corporation, Ligand Pharmaceuticals, Inc. filed Critical American Home Products Corporation
Priority to EP00928519A priority Critical patent/EP1173208A2/fr
Priority to MXPA01011307A priority patent/MXPA01011307A/es
Priority to JP2000614988A priority patent/JP2002543119A/ja
Priority to AU46749/00A priority patent/AU4674900A/en
Priority to CA002372768A priority patent/CA2372768A1/fr
Publication of WO2000066103A2 publication Critical patent/WO2000066103A2/fr
Publication of WO2000066103A3 publication Critical patent/WO2000066103A3/fr
Priority to HK02104867.0A priority patent/HK1043735A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/32—Antioestrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/36—Antigestagens

Definitions

  • This invention relates to regimens of administering compounds which are antagonists of the progesterone receptor in combination with a progestin, an estrogen, or both.
  • Intracellular receptors form a class of structurally related gene regulators known as "ligand dependent transcription factors" (R. M. Evans, Science, 240, 889, 1988).
  • the steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), gluco corticoid receptor (GR), and mineralocorticoid receptor (MR).
  • PR progesterone receptor
  • ER estrogen receptor
  • AR gluco corticoid receptor
  • MR mineralocorticoid receptor
  • the natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as ligands.
  • a ligand Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex. This complex binds to specific gene promoters present in the cell's DNA. Once bound to the DNA the complex modulates the production of mRNA and protein encoded by that gene.
  • PR agonists naturally and synthetic are known to play an important role in the health of women. PR agonists are used in birth control formulations, typically in the presence of an ER agonist. ER agonists are used to treat the symptoms of menopause, but have been associated with a proliferative effect on the uterus which can lead to an increased risk of uterine cancers. Co-administration of a PR agonist reduces/ablates that risk.
  • PR antagonists may also be used in contraception In this context they may be admimstered alone (Ulmann, et al, Ann N Y Acad Sci , 261, 248, 1995), in combination with a PR agonist (Kekkonen, et al, Fertility and Sterility, 60, 610, 1993) or in combination with a partial ER antagonist such as tamoxifen (WO 96/19997 Al, July 4, 1996) PR antagonists may also be useful for the treatment of hormone dependent breast cancers (Horwitz, et al, Hor Cancer, 283, pub Birkhaeuser, Boston, Mass , ed Nedeckis) as well as uterine and ovarian cancers PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy, et al, J Clin Endo Metab , 76, 513, 1993) and endomet ⁇ osis (Kettel, et al, Fertility and Sterility, 56, 402, 1991)
  • U S Patent No 5,521,166 teaches cyclophasic hormonal regimens compnsing an antiprogestin and a progestin wherein the progestin is administered in the alternating presence and absence of an antiprogestin
  • the disclosed regimens also provide for use of an estrogen for a penod of from 2-4 days to prevent breakthrough bleeding
  • This invention provides combination therapies and dosing regimens utilizing antiprogestational agents in combination with one or more progestational agents
  • This invention further provides methods of treatment and dosing regimens further utilizing in combination with these antiprogestrns and progestins, an estrogen, such as ethinyl estradiol
  • regimens and combinations may be admmistered to a mammal to induce contraception or for the treatment and/or prevention of secondary amenorrhea, dysfunctional bleeding, uterine leiomyomata, endometnosis, polycystic ovary syndrome, carcinomas and adeno carcinomas of the endometnum, ovary, breast, colon, prostate Additional uses of the invention include stimulation of food intake
  • the uses herein for the treatment and/or prevention of the conditions or diseases descnbed above includes the continuous administration or periodic discontinuation of administration of the invention to allow for minimization of effect dose or minimization of side effects or cyclic menstrual bleeding
  • the use of this invention for contraception includes administration, preferably orally, to a female of child bearing age an antiprogestin in combmation with an estrogen or progestin or both These administration regimens are preferably carried out over 28 consecutive days, with a terminal portion of the cycle containing administration of no progestins, estrogens or anti-progestins
  • the progestins of these combinations may be administered alone or in combination with an estrogen for the first 14-24 days of the cycle, the progestins being admmistered at a dosage range equal in progestational activity to about 35 ⁇ g to about 150 ⁇ g levonorgestrel per day, preferably equal m activity to from about 35 ⁇ g to about 100 ⁇ g levonorgestrel per day
  • An antiprogestin may then be administered alone or m combmation with an estrogen for a penod of 1 to 11 days to begm on any cycle day between day 14 and 24
  • the anti-progestin m these combmations may be admmistered at a dose of from about 2 ⁇ g to about 50 ⁇ g per day and the estrogen may be administered at a dose of from about 10 ⁇ g to about 35 ⁇ g per day
  • a package or kit containing 28 tablets will mclude a placebo tablet on those days when the antiprogestin or progestm or estrogen is not
  • the progestins of this mvention may be admmistered alone or in combmation with estrogen for the initial 18 to 21 days of a 28-day cycle, followed by administration of an antiprogestin, alone or m combmation with an estrogen, for from 1 to 7 days
  • the estrogen to be used m the combmations and formulations of this mvention is preferably ethinyl estradiol Progestational agents useful with this mvention mclude, but are not limited to, levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethindrone acetate, norgestimate, osaterone, cyproterone acetate, tnmegestone, dienogest.
  • drospirenone nomegestrol, or (17-deacetyl)norgest ⁇ mate
  • progestms for use m the combmations of this mvention are levonorgestrel, gestodene and tnmegestone
  • Examples of orally administered regimens of this mvention over a 28 day cycle m clude administration of a progestational agent solely for the first 21 days at a daily dose equal m progestational activity to from about 35 to about 100 ⁇ g of levonorgestrel
  • An antiprogestin compound of this mvention may then be administered at a daily dose of from about 2 to 50 mg from day 22 to day 24, followed by no administration or administration of a placebo for days 25 to 28 It is most preferred that the daily dosages of each relevant active ingredient be incorporated mto a combined, smgle daily dosage unit, totaling 28 daily units per 28-day cycle
  • a progestational agent may be coadrmnistered for the first 21 days at a daily dose equal m progestational activity to from about 35 to about 150 ⁇ g levonorgestrel, preferably equal in activity to from about 35 to about 100 ⁇ g levonorgestrel, with an estrogen, such as ethinyl estradiol, at
  • Still another regimen withm the scope of this mvention will mclude coadministration from days 1 to 21 of a progestational agent, the progestational agent, preferably levonorgestrel, bemg admmistered at a daily dose equal m progestational activity to from about 35 to about 100 ⁇ g levonorgestrel, and an estrogen, such as ethinyl estradiol, at a daily dose range of from about 10 to about 35 ⁇ g
  • an antiprogestin (2 to 50 mg/day) and an estrogen, such as ethinyl estradiol at a daily dose of from about 10 to about 35 ⁇ g From day 25 to day 28, this regimen may be followed by no administration or administration of a placebo
  • kits or packages of pharmaceutical formulations designed for use m the regimens descnbed herein are preferably designed for daily oral administration over a 28-day cycle, preferably for one oral administration per day, and organized so as to mdicate a smgle oral formulation or combmation of oral formulations to be taken on each day of the 28-day cycle
  • each kit will mclude oral tablets to be taken on each the days specified, preferably one oral tablet will contain each of the combmed daily dosages mdicated
  • one 28-day kit may compnse a) an initial phase of from 14 to 21 daily dosage units of a progestational agent equal m progestational activity to about 35 to about 150 ⁇ g levonorgestrel, preferably equal in progestational activity to about 35 to about 100 ⁇ g levonorgestrel, b) a second phase of from 1 to 11 daily dosage units of an antiprogestm compound of this mvention, each daily dosage umt containmg an antiprogestm compound at a daily dosage of from about 2 to 50 mg, and c) optionally, a third phase of an orally and pharmaceutically acceptable placebo for the remainmg days of the cycle m which no antiprogestin, progestm or estrogen is admmistered
  • a preferred embodiment of this kit may compnse a) an initial phase of 21 daily dosage units of a progestational agent equal m progestational activity to about 35 to about 150 ⁇ g levonorgestrel, preferably equal in progestational activity to about 35 to about 100 ⁇ g levonorgestrel, b) a second phase of 3 daily dosage units for days 22 to 24 of an antiprogestm compound of this mvention, each daily dosage umt containmg an antiprogestm compound at a daily dosage of from about 2 to 50 mg; and c) optionally, a third phase of 4 daily units of an orally and pharmaceutically acceptable placebo for each of days 25 to 28
  • Another 28-day cycle packagmg regimen or kit of this mvention compnses a) a first phase of from 18 to 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 ⁇ g levonorgestrel, preferably equal m activity to from about 35 to about 100 ⁇ g levonorgestrel, and, as an estrogen, ethmyl estradiol at a daily dose range of from about 10 to about 35 ⁇ g, and b) a second phase of from 1 to 7 daily dosage units of an antiprogestm of this mvention at a daily dose of from about 2 to 50 mg, and c) optionally, an orally and pharmaceutically acceptable placebo for each of the remainmg 0-9 days m the 28-day cycle in which no progestational agent, estrogen or antiprogestm is admmistered
  • a prefened embodiment of the kit descnbed above may compnse a) a first phase of 21 daily dosage units of a progestational agent equal m progestational activity to about 35 to about 150 ⁇ g levonorgestrel, preferably equal m activity to from about 35 to about 100 ⁇ g levonorgestrel, and, as an estrogen, ethmyl estradiol at a daily dose range of from about 10 to about 35 ⁇ g, and b) a second phase of 3 daily dosage units for days 22 to 24 of an antiprogestm admmistered at a daily dose of from about 2 to 50 mg, and c) optionally, a third phase of 4 daily dose units of an orally and pharmaceutically acceptable placebo for each of days 25 to 28
  • a further 28-day packaged regimen or kit of this mvention compnses a) a first phase of from 18 to 21 daily dosage units, each containing a progestational agent of this mvention at a daily dose equal m progestational activity to about 35 to about 150 ⁇ g levonorgestrel, preferably equal m activity to from about 35 to about 100 ⁇ g levonorgestrel, and ethmyl estradiol at a daily dose range of from about 10 to about 35 ⁇ g, b) a second phase of from 1 to 7 daily dose units, each daily dose umt containmg an antiprogestm of this mvention at a concentration of from 2 to 50 mg, and ethmyl estradiol at a concentration of from about 10 to about 35 ⁇ g, and c) optionally, an orally and pharmaceutically acceptable placebo for each of the remainmg 0-9 days m the 28-day cycle m which no progestational agent, estrogen or antiprogestm is admmist
  • a preferred embodiment of the package or kit just described compnses a) a first phase of 21 daily dosage units, each containmg a progestational agent of this mvention at a daily dose equal m progestational activity to about 35 to about 150 ⁇ g levonorgestrel, preferably from about 35 to about 100 ⁇ g levonorgestrel, and ethmyl estradiol at a daily dose range of from about 10 to about 35 ⁇ g, b) a second phase of 3 daily dose units for days 22 to 24, each dose unit containing an antiprogestm of this mvention at a concentration of from 2 to 50 mg, and ethmyl estradiol at a concentration of from about 10 to about 35 ⁇ g, and c) optionally, a third phase of 4 daily units of an orally and pharmaceutically acceptable placebo for each of days 25 to 28 In each of the regimens and kits just descnbed, it is preferred that the daily dosage of each pharmaceutically active component of the regimen remain fixed m each particular phase
  • dosage regimens may be adjusted to provide the optimal therapeutic response
  • several divided doses of each component may be administered daily or the dose may be proportionally mcreased or reduced as mdicated by the exigencies of the therapeutic situation
  • reference to a daily dosage unit may also mclude divided units winch are administered over the course of each day of the cycle contemplated
  • Compounds of this mvention which may be used as the anti-progestational agents in the kits, methods and regimens herem are those of the Formula I
  • A, B and D are N or CH, with the proviso that A, B and D can not all be CH,
  • R 1 and R 2 are mdependent substituents selected from H, Ci to C 6 alkyl, substituted Ci to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocychc, substituted heterocyclic, COR A ,
  • NR B COR A or R 1 and R 2 are fused to form a spirocychc ⁇ ng selected from a), b) or c), each spirocychc nng optionally substituted by from 1 to 3 C1-C3 alkyl groups a) a 3 to 8 membered spirocychc alkyl nng, b) a 3 to 8 membered spirocychc alkenyl nng, or c) an optionally substituted 3 to 8 membered heterocychc nng containmg one to three heteroatoms from the group mcludmg O, S and N, the spirocychc nngs of a), b) and c) bemg optionally substituted by from 1 to 4 groups selected from fluorine, Ci to C 6 alkyl, Ci to C ⁇ alkoxy, Ci to C 6 thioalkyl, -CF 3 , -OH, - CN, NH 2 , -NH(C, tok
  • R A is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl, Ci to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 ammoalkyl, or substituted Ci to C 3 ammoalkyl,
  • R B is H, Ci to C 3 alkyl, or substituted C, to C 3 alkyl
  • R 3 is H, OH, NH 2 , Ci to C 6 alkyl, substituted C, to C 6 alkyl, C 3 to C 6 alkenyl, substituted C, to C 6 alkenyl, or COR c ,
  • R c is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl, Ci to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 ammoalkyl, or substituted Ci to C 3 ammoalkyl
  • R 4 is a tnsubstituted benzene rmg containmg the substituents X, Y and Z as shown below
  • X is taken from the group mcludmg halogen, CN, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, Ci to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 thioalkoxy, substituted Ci to C 3 thioalkoxy, ammo, Ci to C 3 ammoalkyl, substituted Ci to C 3 ammoalkyl, NO 2 , Ci to C 3 perfluoroalkyl, 5 or 6 membered heterocychc nng containmg 1 to 3 heteroatoms, COR D , OCOR D , or NR E COR D ,
  • R D is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl, C, to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 ammoalkyl, or substituted Ci to C 3 ammoalkyl,
  • R E is H, Ci to C 3 alkyl, or substituted Ci to C 3 alkyl,
  • Y and Z are mdependent substituents taken from the group mcludmg H, halogen, CN, NO 2 , Ci to C 3 alkoxy, Ci to C 3 alkyl, or Ci to C 3 thioalkoxy, or R 4 is a five or six membered nng with 1, 2, or 3 heteroatoms from the group mcludmg O, S, SO, S0 2 or NR 5 and containmg one or two mdependent substituents from the group mcludmg H, halogen, CN, NO 2 and Ci to C 3 alkyl, Ci to C 3 alkoxy, Ci to C 3 ammoalkyl, COR F , or NR G COR F ,
  • R F is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl, Ci to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 ammoalkyl. or substituted Ci to C 3 ammoalkyl,
  • R G is H, Ci to C alkyl, or substituted d to C 3 alkyl
  • R 5 is H or Ci to C 3 alkyl
  • W is O or a chemical bond, or a pharmaceutically acceptable salt thereof
  • Preferred antiprogestm compounds are those of the formula
  • A, B and D are N or CH, with the proviso that A, B and D can not all be CH,
  • R 1 is H, C, to C 6 alkyl, substituted Ci to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocychc, substituted heterocyclic.
  • COR A or NR B COR A ,
  • R 2 is H, Ci to C 6 alkyl, substituted Ci to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocychc, substituted heterocychc, COR A , or NR B COR A , or R 1 and R 2 are fused to form the optionally substituted 3 to 8 membered spirocychc alkyl, alkenyl or heterocychc nngs descnbed above,
  • R A is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl, d to C 3 alkoxy. substituted Ci to C 3 alkoxy, Ci to C 3 ammoalkyl, or substituted Ci to C 3 ammoalkyl.
  • R B is H, Ci to C 3 alkyl, or substituted d to C 3 alkyl
  • R 3 is H, OH, NH 2 , Ci to C 6 alkyl, substituted Ci to C 6 alkyl, C 3 to C 6 alkenyl, substituted Ci to C 6 alkenyl, or COR c ,
  • R c is H, Ci to C alkyl, substituted Ci to C 4 alkyl, aryl, substituted aryl, Ci to C 4 alkoxy, substituted Ci to C 4 alkoxy, Ci to C ammoalkyl, or substituted Ci to C 4 ammoalkyl,
  • R 4 is a tnsubstituted benzene nng containmg the substituents X, Y and Z as shown below
  • X is selected from halogen, CN, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, Ci to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 thioalkoxy, substituted Ci to C 3 thioalkoxy, Ci to C 3 ammoalkyl, substituted Ci to C 3 ammoalkyl, NO 2 , Ci to C 3 perfluoroalkyl, a 5 membered heterocychc nng containmg 1 to 3 heteroatoms, COR D ,
  • R D is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl, Ci to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 ammoalkyl, or substituted Ci to C 3 ammoalkyl,
  • R E is H, Ci to C 3 alkyl, or substituted Ci to C 3 alkyl,
  • Y and Z are mdependent substituents selected from H, halogen, CN, NO 2 , Ci to C 3 alkoxy, Ci to C 3 alkyl, or Ci to C 3 thioalkoxy, or
  • R 4 is a five or six membered nng with 1, 2, or 3 heteroatoms from the group mcludmg O, S, SO, SO 2 or NR 5 and containmg one or two mdependent substituents from the group mcludmg H, halogen, CN, NO2 and Ci to C 3 alkyl, or Ci to C 3 alkoxy, R 5 is H or Ci to C 3 alkyl, W is O or a chemical bond, or a pharmaceutically acceptable salt thereof Still, more prefened antiprogestm compounds are those of the formula
  • A, B and D are N or CH, with the proviso that A, B and D cannot all be CH,
  • R 1 R 2 and are selected from the group of Ci to C 3 alkyl, substituted Ci to C 3 alkyl, or spirocychc alkyl constructed by fusmg R 1 and R 2 to form a 3 to 6 membered spirocychc nng,
  • R 3 is H, OH, NH 2 , C, to C 6 alkyl, substituted d to C 6 alkyl, or COR c ,
  • R c is H, Ci to C 4 alkyl, or Ci to C 4 alkoxy,
  • R 4 is a disubstituted benzene nng containmg the substituents X, and Y as shown below
  • X is selected from the group of halogen, CN, Ci to C 3 alkoxy, Ci to C 3 alkyl, NO 2 , Ci to C 3 perfluoroalkyl, 5 membered heterocychc nng containmg 1 to 3 heteroatoms, or Ci to C 3 thioalkoxy,
  • Y is a substituent on the 4' or 5 'position from the group mcludmg H. halogen, CN, NO 2 , C, to C 3 alkoxy, d to C 4 alkyl, or Ci to C 3 thioalkoxy, or R is a five membered rmg with the structure
  • U is O, S, or NR ,5 D
  • R 5 is H, or Ci to C 3 alkyl, or d to C 4 CO 2 alkyl,
  • X' is selected from halogen, CN, NO 2 , Ci to C 3 alkyl, or Ci to C 3 alkoxy,
  • Y' is selected from H and Ci to C alkyl, or
  • R 4 is a six membered nng with the structure
  • X 2 is halogen, CN or NO 2 , or a pharmaceutically acceptable salt thereof
  • N B and D are ⁇ or CH, with the proviso that A, B and D can not all be CH,
  • R 1 R 2 and are selected from CH 3 and spirocychc alkyl constructed by fusmg R 1 and R 2 to form a 6 membered spirocychc nng,
  • R 3 is H, OH, ⁇ H 2 , CH 3 , substituted methyl, or COR c ,
  • R c is H, Ci to C 3 alkyl, or Ci to C 4 alkoxy,
  • R 4 is a disubstituted benzene nng containmg the substituents X and Y as shown below
  • X is halogen, CN, methoxy, NO 2 , or 2-th ⁇ azole
  • Y is a substituent on the 4' or 5'pos ⁇ t ⁇ on selected from H and F
  • R 4 is a five membered rmg of the structure
  • X " is halogen, CN, or NO 2 ,
  • Y' is H or Ci to C 4 alkyl
  • W is O or a chemical bond, or a pharmaceutically acceptable salt thereof
  • the antiprogestm compounds of this mvention may contam an asymmetric carbon atom and some of the compounds of this mvention may contam one or more asymmetnc centers and may thus give rise to optical isomers and diastereomers While shown without respect to stereochemistry m Formula I, the present mvention mcludes such optical isomers and diastereomers, as well as the racemic and resolved, enantiome ⁇ cally pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof
  • alkyl is used herem to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups havmg one to eight carbon atoms, preferably one to six carbon atoms
  • alkenyl is mtended to mclude both straight- and branched- chain alkyl group with at least one carbon-carbon double bond and two to eight carbon atoms, preferably two to six carbon atoms
  • alkynyl is mtended to cover both straight- and branched-chain alkyl group with at least one carbon-carbon tnple bond and two to eight carbon atoms, preferably two to six carbon atoms
  • substituted alkyl refers to alkyl, alkenyl, and alkynyl as just descnbed havmg one or more substituents from the group mcludmg halogen, CN, OH, N0 2 , ammo, aryl, heterocyclic, substituted aryl, substituted heterocychc, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, arylthio
  • substituents may be attached to any carbon of alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable chemical moiety
  • aryl is used herem to refer to an aromatic system which may be a smgle nng or multiple aromatic rmgs fused or lmked together as such that at least one part of the fused or linked
  • heterocychc c is used herem to descnbe a stable 4- to 7-membered monocychc or a stable multicyclic heterocychc nng which is saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group mcludmg N, O, and S atoms The N and S atoms may be oxidized
  • the heterocychc nng also mcludes any multicyclic rmg in which any of above defined heterocychc rmgs is fused to an aryl nng
  • the heterocychc rmg may be attached at any heteroatom or carbon atom provided the resultant structure is chemically stable
  • Such heterocychc groups mclude, for example, tetrahydrofuran, prpendinyl, piperazmyl, 2-oxop ⁇ pend ⁇ nyl, azepmyl, py ⁇ o dinyl,
  • substituted heterocychc is used herem to descnbe the heterocychc just defined havmg one to four substituents selected from the group which mcludes halogen, CN, OH, NO 2 , ammo, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio
  • alkoxy is used herem to refer to the OR group, where R is alkyl or substituted alkyl
  • aryloxy is used herem to refer to the OR group, where R is aryl or substituted aryl
  • alkylcarbonyl is used herem to refer to the RCO group, where R is alkyl or substituted alkyl
  • alkylcarboxy is used herem to refer to the
  • the antiprogestm compounds of the present mvention can be used m the form of salts denved from pharmaceutically or physiologically acceptable acids or bases
  • These salts mclude, but are not limited to, the following salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and, as the case may be, such organic acids as acetic acid, oxalic acid, succinic acid, and maleic acid
  • Other salts mclude salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium m the form of esters, carbamates and other conventional "pro-drug" forms, which, when admmistered m such form, convert to the active moiety in vivo
  • These methods may be used for contraception or treatment and/or prevention of secondary amenonhea, dysfunctional bleedmg, uterine leiomyomata, endometnosis, polycystic ovary syndrome, carcinomas and adeno carcinomas of the endometnum, ovary, breast, colon, prostate, or minimization of side effects or cychc menstrual bleedmg Additional uses of the mvention mclude stimulation of food intake
  • the compounds When the compounds are employed for the above utilities, they may be combmed with one or more pharmaceutically acceptable earners or excipients, for example, solvents, diluents and the like, and may be admmistered orally m such forms as tablets, capsules, dispersible powders, granules, or suspensions containmg, for example, from about 0 05 to 5% of suspendmg agent, syrups containmg, for example, from about 10 to 50% of sugar, and elixirs containmg, for example, from about 20 to 50% ethanol, and the like, or parenterally m the form of stenle injectable solutions or suspensions containmg from about 0 05 to 5% suspendmg agent m an lsotonic medium
  • Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient m combmation with the earner, more usually between about 5% and 60% by weight
  • active agents of the methods and regimens herem may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes
  • Solid earners m clude starch, lactose, dicalcium phosphate, microcrystalhne cellulose, sucrose and kaolin, while liquid earners mclude stenle water, polyethylene glycols, non-ionic surfactants and edible oils such as com, peanut and sesame oils, as are appropnate to the nature of the active mgredient and the particular form of administration desired
  • Adjuvents customarily employed in the preparation of pharmaceutical compositions may be advantageously mcluded, such as flavoring agents, colormg agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA
  • compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard- filled or hquid-filled capsules Oral administration of the compounds is preferred
  • active compounds may also be administered parenterally or intrapentoneally Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose Dispersions can also be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof m oils Under ordmary conditions of storage and use, these preparations contam a preservative to prevent the growth of microorganisms
  • the pharmaceutical forms suitable for mjectable use mclude sterile aqueous solutions or dispersions and stenle powders for the extemporaneous preparation of sterile mjectable solutions or dispersions
  • the form must be sterile and must be fluid to the extent that easy syringe ability exits It must be stable under conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacterial and fungi
  • the carrier can be a solvent or dispersion medium containmg, for example, water, ethanol (e g , glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil
  • the antiprogestin compounds of this invention are generally prepared by employmg the suitable couphng reaction as a final step
  • Rmg closure of carbinol 2 to yield oxazm-2-ones 3 is commonly effected by a condensing agent such as carbonyldnmidazole, phosgene, dimethylcarbonate, or diethylcarbonate m a suitable
  • CDL THF 50 degrees C, N 2 ,
  • the transformation of 3 mto 5 can be effected by treatmg 3 with an organo metalhc reagent, e g , n-BuLi, m a nonprotic solvent such as THF or ether followed by quenching the reaction solution with a suitable electrophile such as tnmethyl borate, tnisopropyl borate, bishexalkyl tm reagent, or zmc chlonde at temperatures rangmg fiOm-78 °C to room temperature under an inert atmosphere such as argon or nitrogen
  • Conversion of carbamate 6 to thiocarbamate 7 can be readily effected by treatment of 6 with a suitable sulfur reagent such as P 2 S 5 or Lawesson's reagent m a suitable non- protic solvent such as toluene, chlorobenzene, benzene, or xylene under an inert atmosphere such as argon or nitrogen at the temperature of boiling solvent
  • the Weinreb amide 9 can be prepared from an appropnately substituted isatoic anhydnde when treated with N-, O-dimethylhydroxyl- amine hydrochlonde salt m a protic solvent such as ethanol or isopropanol at reflux under an inert atmosphere such as argon or mtrogen
  • Couphng of amide 9 with an aryl electrophile such as aryl boromc acid or arylstannane to give 10 can be effected by employing a typical couphng reaction such as Suzuki, Stille couphng procedure m a similar fashion as descnbed for the preparation of oxazmones 4
  • Conversion of ketone 11 to carbinol 12 can be effected by treatment of 10 with an organo metalhc reagent such as alkyl, alkynyl, or aryl Gngnard compound m a nonprotic solvent such as THF or ether under an inert atmosphere such as argon or nitrogen at -78°C to room temperature
  • Conversion of ketone 11 to carbinol 12 can also be effected by reduction of ketone group of 11 to the carbinol moiety of 12 usmg an appropriate reducmg reagent such as lithium aluminum hydride, sodium borohydnde m a suitable solvent such as THF, ether, or anhydrous alcohol under an inert atmosphere m the temperature ranging from 0°C to the boiling pomt of the solvent Rmg closure of carbinol 12 to produce the compounds of this mvention, 13, can be accomphshed with condensing agents such as carbonyldiimidazole, phosgene, di
  • ortho-ammo ketone 11 can be prepared by treatment of ortho- ammo nitnle 16 with an organo metallic compound such as organo hthium reagent or Grmgard reagent m a suitable solvent such as THF or ether under an mert atmosphere such as argon or mtrogen at temperatures rangmg from -78 °C to room temperature as illustrated m Scheme III
  • organo metallic compound such as organo hthium reagent or Grmgard reagent m
  • suitable solvent such as THF or ether
  • mert atmosphere such as argon or mtrogen
  • Nitnle 16 can be readily prepared from an appropriately substituted mtnle such as bromobenzoratnle 15 usmg a suitable couplmg reaction such as Stille or Suzuki protocol earned out m a similar fashion as descnbed for the preparation of the Weinreb amide 10
  • the compounds of this mvention were tested m the relevant assay as descnbed below and their potency are m the range of 0 01 nM to 5 ⁇ M m the in vitro assays and 0 001 to 300 mg/kg m the in vivo assays
  • the selected example is example 4
  • the m- vitro biology is determmed by (1) competitive Radiohgand Bmdmg usmg the A-form of the human progesterone receptor with progesterone as the radiohgand, (2) co-transfection assay, which provides functional activity expressed as agomst EC50 and Antagomst IC50 values, (3) a T47D cell proliferation, which is a further functional assay which also provides agonist and antagomst data, and (4) T47D cell alkaline phosphatase assay, which is a further functional assay which also provides agonist and antagomst data
  • hPR Bmdmg assay This assay is carried out m accordance with Pathirana, C , Stem, R B , Berger, T S , Fenical, W , Ianiro, T , Mais, D E , Torres, A , Glodman, M E , Nonsteroidal human progesterone receptor modulators from the marine alga cymop a barbata, J Steroid Biochem Mol Biol , 1992, 41, 733-738
  • the object of this assay is to determine a compound's progestational or antiprogestational potency based on its effect on PRE-luciferase reporter activity m CN-1 cells co-transfected with human PR and PRE-luciferase plasmids
  • the materials methods used in the assay are as follows a Medium
  • the growth medium was as follows
  • DMEM BioWhittaker
  • fetal bovme serum heat mactivated
  • 0 1 mM MEM non-essential ammo acids 0 1 mM MEM non-essential ammo acids
  • lOOU/ml pemcillm lOOmg/ml streptomycm
  • 2 mM GlutaMax GIBCO, BRL
  • DMEM BioWhittaker
  • phenol red-free containmg 10% (v/v) charcoal-stnpped fetal bovme serum (heat -mactivated), 0 1 mM MEM non-essential ammo acids, lOOU/ml pemcillm, lOOmg/ml streptomycm, and 2 mM GlutaMax (GIBCO, BRL) b Cell culture, transfection. treatment, and luciferase assay
  • Each treatment consists of at least 4 replicates
  • Log transformed data are used for analysis of vanance and nonlinear dose response curve fitting for both agonist and antagomst modes
  • Huber weightmg is used to downweight the effects of outliers.
  • EC 50 or IC 5 o values are calculated from the retransformed values.
  • JMP software SAS Institute, Inc.
  • Reference Compounds: Progesterone and tnmegestone are reference progestins and
  • RU486 is the reference antiprogestin. All reference compounds are run in full dose- response curves and the EC 5 o or IC 5 o values are calculated.
  • Antiprogestational activity Compounds that decrease 3 nM progesterone mduced PRE-luciferase activity significantly (p ⁇ 0 05) EC 5 o Concentration of a compound that gives half-maximal mcrease PRE- luciferase activity (default-nM) with SE
  • 3 T47D cell proliferation assay The objective of this assay is the determination of progestational and antiprogestational potency by usmg a cell proliferation assay m T47D cells A compound's effect on DNA synthesis m T47D cells is measured
  • the matenals and methods used in this assay are as follows a Growth medium DMEM F12 (1 1) (GIBCO, BRL) supplemented with 10% (v/v) fetal bovme serum (not heat- lnactivated), lOOU/ml pemcillm, lOOmg/ml streptomycm, and 2 mM GlutaMax (GIBCO, BRL) b Treatment medium Minimum Essential Medium (MEM) (#51200-038GIBCO, BRL) phenol red-free supplemented with 0 5% charcoal stnpped fetal bovine serum, lOOU/ml pemcillm, 200 mg/ml streptomycm, and 2 mM GlutaMax (
  • This assay is to identify progestins or antiprogestins by determmmg a compound's effect on alkalme phosphatase activity m T47D cells
  • the materials and methods used in this assay are as follows a. Culture medium DMEM F12 (1 1) (GIBCO. BRL) supplemented with 5% (v/v) charcoal stripped fetal bovme serum (not heat-mactivated), lOOU/ml pemcillm, 100 ⁇ g/ml streptomycm, and 2 mM GlutaMax (GIBCO. BRL) b Alkalme phosphatase assay buffer
  • Frozen T47D cells were thawed m a 37°C water bath and diluted to 280,000 cells/ml m culture mediu To each well m a 96-well plate (Falcon, Becton Dickinson Labware), 180 ⁇ l of diluted cell suspension was added Twenty ⁇ l of reference or test compounds diluted m the culture medium was then added to each well When testmg for progestm antagonist activity, reference antiprogestins or test compounds were added m the presence of 1 nM progesterone The cells were mcubated at 37°C m a 5% CO /hum ⁇ d ⁇ fied atmosphere for 24 hr d Alkalme Phosphatase Enzyme Assay
  • a dose response curve is generated for dose (X-axis) vs the rate of enzyme reaction (slope) (Y-axis)
  • Square root-transformed data are used for analysis of vanance and nonlinear dose response curve fitting for both agomst and antagomst modes
  • Huber weightmg is used to downweight the effects of outliers
  • EC 50 or IC 5 o values are calculated from the retransformed values
  • JMP software SAS Institute, Inc
  • Reference Compounds Progesterone and tnmegestone are reference progestms and RU486 is the reference antiprogestm All reference compounds are run m full dose response curves and the EC 50 or IC 50 values are calculated
  • Progesterone 1 0 839 0 030 0 706 0 996
  • the primary m-vivo assay is the rat decidua zation model, which may be used to determme progestational effects of both agomsts and antagomsts
  • the secondary m- vivo assay is the rat ovulation inhibition model, which is under development, and hence the protocol is un-available
  • Rat deciduahzation assay The objective of this procedure is used to evaluate the effect of progestins and antiprogestins on rat uterme deciduahzation and compare the relative potencies of vanous test compounds
  • This assay are as follows a Methods: Test compounds are dissolved m 100% ethanol and mixed with corn oil (vehicle) Stock solutions of the test compounds m oil (MazolaTM) ⁇ Q en prepared by heatmg (-80 °C) the mixture to evaporate ethanol Test compounds are subsequently diluted with 100% corn oil or 10% ethanol m corn oil pnor to the treatment of animals No difference m decidual response was found when these two vehicles were compared b Animals (RACUC protocol #5002)
  • Ovanectomized mature female Sprague-Dawley rats ( ⁇ 60-day old and 230g) are obtamed from Tacomc (Tacomc Farms, NY) followmg surgery
  • Ovanectomy is performed at least 10 days pnor to treatment to reduce circulating sex steroids
  • Animals are housed under 12 hr light/dark cycle and given standard rat chow and water ad libitum c Treatment Rats are weighed and randomly assigned to groups of 4 or 5 before treatment
  • Test compounds m 0 2 ml vehicle are admmistered by subcutaneous injection m the nape of the neck or by gavage usmg 0 5 ml
  • the animals are treated once daily for seven days
  • For testmg antiprogestins animals are given the test compounds and a EC50 dose of progesterone (5 6 mg/kg) during the first three days of treatment
  • animals contmue to receive progesterone until necropsy four days later d
  • Doses are prepared based upon mg/kg mean group body weight In all studies, a control group receivmg vehicle is included Determination of dose-response curves is earned out usmg doses with half log mcreases (e g 0 1, 0 3, 1 0, 3 0 mg/kg ) e Decidual mduction
  • deciduahzation is mduced in one of the uterme horns by scratching the antimesometnal luminal epithehum with a blunt 21 G needle
  • the contralateral hom is not scratched and serves as an unstimulated control
  • rats are sacrificed by CO2 asphyxiation and body weight measured Uten are removed and trimmed of fat Deciduahzed (D-hom) and control (C-hom) uterme horns are weighed separately f Analysis of Results
  • the mcrease m weight of the deciduahzed uterme hom is calculated by D-horn/C-horn and loganthmic transformation is used to maximize normality and homogeneity of vanance
  • the Huber M-estimator is used to down weight the outlymg transformed observations for both dose-response curve fittmg and one-way analysis of vanance JMP software (SAS Institute, Inc ) is used for both oneway ANONA and non-linear dose-response analyses g Reference Compounds
  • Concentration Compound concentration m assay(default-mg/kg body weight) Route of administration Route the compound is admmistered to the animals
  • Body weight Mean total animal body weight (default-kg) D-hom Wet weight of deciduahzed uterme hom (default -mg) C-hom Wet weight of control uterme hom (default-mg) Decidual response [(D-C)/C]xl00% Progestational activity Compounds that mduce deciduahzation significantly
  • Antiprogestational activity Compounds that decrease ECso progesterone mduced deciduahzation significantly (p ⁇ 0 05)
  • IC50 for uterme weight Concentration of compound that gives half-maximal decrease in EC 50 progesterone mduced decidual response (default-mg/kg)

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Abstract

La présente invention concerne des thérapies combinatoires cycliques dans lesquelles sont utilisés des dérivés d'indoline qui sont des antagonistes du récepteur de progestérone, représentés par la structure générale (I) dans laquelle: A, B et D représentent N ou CH, mais ne peuvent pas tous représenter CH; R1 et R2 représentent H, COR?A, NRBCORA¿, ou des groupes alkyles, alcényles, alcynyles, cycloalkyles ou aryles éventuellement substitués; ou R1 et R2 forment un noyau spirocyclique; RA représente H ou aryle, alcoxy, aminoalkyle ou alkyle éventuellement substitué; RB représente H, alkyle; R3 représente H, OH, NH¿2?, alkyle, alcényle, ou COR?C; RC¿ représente H, alkyle, aryle, alcoxy, ou aminoalkyle; R4 représente benzène ou un noyau hétéroaromatique contenant de 5 à 6 éléments; RF représente H, alkyle, aryle, alcoxy, ou aminoalkyle; RG représente H ou alkyle; R5 représente H ou alkyle; W représente O ou une liaison chimique; ou un sel pharmaceutiquement acceptable. Lesdites méthodes peuvent être utilisées à des fins de contraception ou de traitement et/ou à des fins de prévention de l'aménorrhée secondaire, du saignement dysfonctionnel, du leiomyomata utérin, de l'endométriose, du syndrome des ovaires polykystiques, des carcinomes et des adénocarcinomes de l'endomètre, de l'ovaire, du sein, du colon ou de la prostate ou encore, pour réduire les effets secondaires ou les saignements menstruels cycliques. Lesdites méthodes peuvent également être utilisées pour stimuler l'ingestion alimentaire.
PCT/US2000/011449 1999-05-04 2000-05-01 Schemas posologiques cycliques comprenant de l'uree cyclique et des derives cycliques d'amide WO2000066103A2 (fr)

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EP00928519A EP1173208A2 (fr) 1999-05-04 2000-05-01 Schemas posologiques cycliques comprenant de l'uree cyclique et des derives cycliques d'amide
MXPA01011307A MXPA01011307A (es) 1999-05-04 2000-05-01 Regimenes ciclicos utilizando urea ciclica y derivados de amida ciclica.
JP2000614988A JP2002543119A (ja) 1999-05-04 2000-05-01 環状尿素および環状アミド誘導体を用いた周期的管理
AU46749/00A AU4674900A (en) 1999-05-04 2000-05-01 Cyclic regimens using cyclic urea and cyclic amide derivatives
CA002372768A CA2372768A1 (fr) 1999-05-04 2000-05-01 Schemas posologiques cycliques comprenant de l'uree cyclique et des derives cycliques d'amide
HK02104867.0A HK1043735A1 (zh) 1999-05-04 2002-06-28 含環狀尿素與醯胺衍生物之避孕組合物

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AU4674900A (en) 2000-11-17
CN1349412A (zh) 2002-05-15
CA2372768A1 (fr) 2000-11-09
WO2000066103A3 (fr) 2001-04-05
MXPA01011307A (es) 2003-07-14
EP1173208A2 (fr) 2002-01-23
US6399593B1 (en) 2002-06-04
JP2002543119A (ja) 2002-12-17

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